New Rules for Giving Good Cholesterol a Boost

By

Christopher Weaver

Updated Jan. 7, 2013 7:36 p.m. ET

In the war against heart-damaging high cholesterol, a promising weapon has been largely neutralized.

A string of recent clinical studies, including a major
Merck
& Co. trial that began in 2007 and was canceled last month, have shown medicines that raise "good cholesterol" to be no more effective at warding off heart disease than widely used "bad-cholesterol"-cutting drugs alone.

This has left researchers grappling with a riddle: Low levels of high-density lipoprotein, or so-called good cholesterol, have long been shown as a predictor of heart disease, since HDLs help ferry bad cholesterol away from artery walls to the liver. But even with drugs such as niacin—which raised HDL levels 18 percentage points more than a placebo in an early trial that supported its FDA approval—studies now show it hasn't reduced the odds of falling ill when bad cholesterol is in check.

Now, some scientists theorize that the problem lies not in trying to raise HDL, but specifically in the approaches current medications take to raising it.

These findings cast dark clouds over what many scientists have long seen as the next-most promising avenue of cholesterol treatment after statin drugs, which slash the "bad" cholesterol that accumulates in the arteries.
Pfizer
Inc.
's well-known statin Lipitor, now generic, reduced the risk of heart attacks by one-third in studies. Doctors and researchers hoped boosting HDL would go a long way toward limiting remaining risk.

More on Heart Health

In the Merck study, researchers found adding HDL-boosting niacin to a statin didn't prevent heart attacks any more effectively than a statin alone.

"The statin story has been one of the triumphs of medicine, but it was not a cure," says Jorge Plutzky, a cardiologist and researcher at Brigham and Women's Hospital in Boston, noting that people on the drug still suffer heart attacks.

Niacin, a naturally occurring B vitamin, is prescribed for heart-health conditions. Side effects are usually minimal, often limited to facial flushing. In very rare cases, high dosages have been linked to liver toxicity.

ENLARGE

Jack Kutner, one of Dr. Plutzky's patients, took a big dose of niacin each day for more than two decades—in part because of his family's history of fatal heart attacks. But when the 55-year-old retired financial services executive from Cambridge, Mass., reviewed the recent research with Dr. Plutzky, he says they concluded the niacin wasn't doing anything to lower his heart risk and that his cholesterol was well controlled on the statin Crestor. "We figured we'd just get rid of it," says Mr. Kutner.

Dr. Plutzky says he is disappointed by the failure of niacin in recent trials, especially given its promise. "One of the great hopes to bring down residual risks in the post-statin era is by raising HDL," he says, but the data beg the question, "where do we go from here?"

Indeed, research has long shown that people with high HDL levels face fewer heart attacks. A nonsmoking 55-year-old man with normal blood pressure and high HDL—60 or greater—faces a 4% 10-year chance of heart disease, about one-third less than an identical patient with HDL below 30, according to the Framingham Risk Score, a widely used heart-health assessment based on a decades-long longitudinal study.

But drug-industry attempts to artificially inflate HDL have fallen short. In addition to Merck's recent study for a drug called Tredaptive,
Roche Holding
AG
halted a study for an HDL-raising drug known as CETP inhibitor in May when researchers realized it wasn't working. Pfizer canceled a similar study in 2006. And last year, National Institutes of Health-funded research showed niacin didn't improve results for patients already taking statins.

The Merck study "showed a real question mark in the therapeutic marker," said Roger Newton, chief science officer of drug firm Esperion, and a discoverer of Lipitor. Researchers theorize that medically elevated HDL may not be as effective as natural HDL at whisking away bad cholesterol. "Not all HDL are created the same," he said.

But little is known about what makes an effective HDL particle versus a stunted, useless one, Dr. Newton says. While Esperion is working on an HDL-boosting treatment, "we're focusing most of our energies and finances" on a new LDL-lowering medicine, he says.

That leaves patients seeking a heart-health booster beyond statins with old-fashioned lifestyle methods such as diet and exercise. "If you raise HDL in non-pharmacologic ways, it really does help you," says Steve Kopecky, a Mayo Clinic cardiologist. "We always assumed it was HDL" that decreased heart-disease risk, he says. "But maybe it was the exercise that did it, or the not smoking that did it," he says.

Doctors advise routine exercise along with a healthy diet featuring vegetables, fruits, nuts and whole grains. High-sugar diets, obesity and smoking all lower HDL, while moderate drinking—a glass of wine a night, for instance—can raise it. Mr. Kutner, in Cambridge, says his HDL, aided by daily exercise and efforts to avoid foods such as red meat, had reached 38 without niacin, a lifetime record.

"Let's pay at least as much attention to nutrition as we do [to] drugs," says Stephen Devries, a Northwestern Medicine cardiologist and director of the Gaples Institute, a nonprofit that promotes heart health. "There's a big focus on drugs, partly because no one is making a lot of money selling nuts."

But for many patients drugs are easier. "I know I should get at least 30 minutes of physical activity in every day," says Christopher Edginton, a 66-year-old professor of leisure services at the University of Northern Iowa who took niacin for several years. But "I don't always do it," he says.

Researchers who hope for a successful, HDL-raising drug now say they worry pharmaceutical companies may not revisit the approach. Drug maker
AbbVie
Inc.,
will lose patent protection for its $900 million-a-year niacin-based drug Niaspan in 2013, and has no incentive to fund further research.

Sales of prescription niacin, marketed by AbbVie, and over-the-counter B vitamin pills which often contain lower doses, reached more than $2 billion in combined U.S. sales last year, according to company filings and data firm Euromonitor.

Merck says it remains hopeful about its own CETP inhibitor now in clinical trials, but declined to discuss details of the Tredaptive study pending full publication of the results. Tredaptive included niacin, a statin and another drug meant to reduce the flushing side effect of niacin.

William Boden, chief of medicine at Samuel S. Stratton VA Medical Center in Albany, N.Y., and a principal investigator in the NIH-funded niacin study, says a well-designed niacin study may show the drug has benefits for certain patients, such as those with very low HDL, but "the question is now, who would fund it?"

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